Journal of pharmacological sciences最新文献_第6页

Direct effects of cigarette smoke extract from heated tobacco products on cardiomyocyte: Comparison with combustible cigarettes 加热烟草制品烟气提取物对心肌细胞的直接影响：与可燃香烟的比较

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-07-24 DOI: 10.1016/j.jphs.2025.07.007

Jumpei Yasuda , Takuya Notomi , Takahiro Horinouchi , Tomoe Y. Nakamura

Smoking of combustible cigarettes is a risk factor for cardiovascular disease. Heated tobacco products (HTPs) have recently increased in use due to their perceived lower toxicity compared with combustible cigarettes, yet their direct effects on cardiomyocytes remain unclear. In the present study, we compared the effects of nicotine- and tar-free cigarette smoke extracts (CSE) from two HTPs (‘HTP-1’ and ‘HTP-2’) and a combustible reference cigarette (RF) on cultured neonatal rat ventricular myocyte. All CSEs reduced cell viability and the spontaneous beating rate, with toxicity ranked as RF > HTP-2 > HTP-1. HTP-2 and RF also induced intracellular Ca²⁺-overload, contractile dysfunction, and mitochondrial reactive oxygen species production, whereas HTP-1 did not. Mitochondrial respiration and ATP production were suppressed by all CSEs, while glycolysis was upregulated only by HTP-2 and RF, indicating different metabolic alterations. Acrolein, a shared toxicant in all products, also reduced cell viability, suggesting its involvement in CSE-induced cardiotoxicity. In summary, we revealed that HTPs, like combustible cigarettes, exhibit direct cardiomyocyte toxicity, but the underlying mechanisms appear to differ between different cigarette products with regard to abnormal Ca²⁺ regulation and metabolic inhibition. These findings raise concern regarding the cardiac safety of HTPs.

吸可燃香烟是患心血管疾病的一个危险因素。与可燃香烟相比，加热烟草制品（HTPs）的毒性较低，因此最近使用量有所增加，但其对心肌细胞的直接影响尚不清楚。在本研究中，我们比较了两种HTPs（“HTP-1”和“HTP-2”）中不含尼古丁和不含焦油的香烟烟雾提取物（CSE）和可燃参比香烟（RF）对培养的新生大鼠心室肌细胞的影响。所有CSEs均降低细胞活力和自发跳动率，毒性等级为RF >；HTP-2祝辞HTP-1。HTP-2和RF也诱导细胞内Ca2+超载、收缩功能障碍和线粒体活性氧产生，而HTP-1则没有。所有CSEs均抑制线粒体呼吸和ATP产生，而糖酵解仅被HTP-2和RF上调，表明不同的代谢改变。丙烯醛是所有产品中共有的一种有毒物质，它也降低了细胞活力，表明它参与了cse诱导的心脏毒性。总之，我们发现HTPs，像可燃香烟一样，表现出直接的心肌细胞毒性，但关于异常Ca2+调节和代谢抑制，不同香烟产品之间的潜在机制似乎不同。这些发现引起了人们对htp心脏安全性的关注。

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引用次数: 0

Therapeutic potential of SMTP-27 in attenuating diabetic nephropathy with anti-inflammatory activity SMTP-27抗炎治疗糖尿病肾病的潜力

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-07-24 DOI: 10.1016/j.jphs.2025.07.006

Keita Shibata , Taiki Awane , Takashi Takaki , Keiji Hasumi , Koji Nobe

Diabetic nephropathy (DN) is a leading cause of chronic kidney disease (CKD), affecting nearly one-third of CKD patients. As CKD advances, it may progress to end-stage renal disease, necessitating dialysis or transplantation. Hyperglycemia-driven metabolic and hemodynamic disturbances contribute to oxidative stress, inflammation, and fibrosis. Since current treatments remain insufficient, novel therapeutic strategies are urgently needed to halt DN progression. Stachybotrys microspora triprenyl phenols (SMTPs), the focus of our research, exhibit anti-inflammatory properties and have shown therapeutic potential in various disease models. We aimed to evaluate the efficacy of SMTP-27 in a DN mouse model. DN was induced by removing the right kidney of db/db mice. The efficacy of SMTP-27 was determined by evaluating the renal function using urine and serum samples and morphological assessment of the kidney tissues. For deciphering the mechanism of action of SMTP-27, markers associated with inflammatory signaling pathways in the kidney were detected. SMTP-27 (0.03, 0.3, 3, 30 mg/kg) dose-dependently improved the renal function. In addition, it improved the mesangial matrix overproduction, podocyte injury, and renal tubule injury and exhibited anti-inflammatory activity in the kidneys of mice with DN. These results indicate the potential of SMTP-27 as a novel therapeutic strategy for DN.

糖尿病肾病（DN）是慢性肾脏疾病（CKD）的主要原因，影响近三分之一的CKD患者。随着CKD的进展，它可能发展为终末期肾脏疾病，需要透析或移植。高血糖引起的代谢和血流动力学紊乱可导致氧化应激、炎症和纤维化。由于目前的治疗仍然不足，迫切需要新的治疗策略来阻止DN的进展。小孢子Stachybotrys microspora triprenyl phenols （SMTPs）是我们研究的重点，它具有抗炎特性，并在多种疾病模型中显示出治疗潜力。我们的目的是评估SMTP-27在DN小鼠模型中的疗效。通过切除db/db小鼠右肾诱导DN。SMTP-27的疗效通过尿液、血清和肾组织形态学评估来确定。为了破译SMTP-27的作用机制，检测了肾脏中与炎症信号通路相关的标志物。SMTP-27（0.03、0.3、3、30 mg/kg）呈剂量依赖性改善肾功能。此外，它还能改善DN小鼠肾系膜基质过剩、足细胞损伤和肾小管损伤，并表现出抗炎活性。这些结果表明SMTP-27作为一种新的DN治疗策略的潜力。

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引用次数: 0

Oren-gedoku-to inhibits calcification of human aortic valve interstitial cells in vitro and aortic valve in spontaneously hypertensive rats in vivo oren - gedokuto体外抑制人主动脉瓣间质细胞钙化，体内抑制自发性高血压大鼠主动脉瓣钙化

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-07-18 DOI: 10.1016/j.jphs.2025.07.004

Zaiqiang Yu , Shihu Men , Kazuyuki Daitoku , Tadaatsu Imaizumi , Masahito Minakawa , Kazuhiko Seya

Despite being the most common adult heart valve disease in developed countries, no medicinal treatment exists for calcific aortic valve stenosis (CAS). We previously demonstrated that tumor necrosis factor (TNF)-α promotes aortic valve calcification (AVC) via the bone morphogenic protein (BMP) 2-alkaline phosphatase (ALP) pathway. In the present study, we aimed to investigate the effects of Kampo, a traditional Japanese herbal medicine, on TNF-α-induced AVC involving CAS progression. We confirmed that Oren-gedoku-to (OGT, 10–100 μg/mL) strongly and dose-relatedly inhibited HAVIC calcification induced by TNF-α (30 ng/mL). OGT significantly inhibited TNF-α-induced BMP2 expression, p65 NF-κB phosphorylation, and ALP activation in HAVICs. Notably, two crude drugs from OGT [Coptis rhizome (CR), and Phellodendron bark (PB)] exhibited inhibitory effects akin to those of OGT. Berberine, mainly contained in CR and PB, also inhibited TNF-α induced HAVIC calcification, BMP2 expression, and p65 NF-κB phosphorylation. Further, OGT significantly prevented accelerated AVC in spontaneously hypertensive rats in vivo. Our results suggest that OGT and its component, berberine, can effectively prevent AVC acceleration both in vitro and in vivo.

尽管钙化性主动脉瓣狭窄（CAS）是发达国家最常见的成人心脏瓣膜疾病，但目前尚无药物治疗方法。我们之前已经证明肿瘤坏死因子(TNF)-α通过骨形态发生蛋白（BMP） 2-碱性磷酸酶（ALP）途径促进主动脉瓣钙化（AVC）。在本研究中，我们旨在研究日本传统中草药甘布对TNF-α-诱导的AVC涉及CAS进展的影响。我们证实了orengedoku -to （OGT, 10-100 μg/mL）对TNF-α (30 ng/mL)诱导的HAVIC钙化具有强烈且剂量相关的抑制作用。OGT显著抑制TNF-α-诱导的肝纤维化患者BMP2表达、p65 NF-κB磷酸化和ALP激活。值得注意的是，从OGT中提取的两种药材[黄连（Coptis rhizome， CR）和黄柏树皮（Phellodendron bark， PB）]表现出与OGT相似的抑制作用。主要存在于CR和PB中的小檗碱还能抑制TNF-α诱导的HAVIC钙化、BMP2表达和p65 NF-κB磷酸化。此外，OGT在体内显著阻止自发性高血压大鼠AVC加速。我们的研究结果表明，OGT及其成分小檗碱在体外和体内都能有效地防止AVC加速。

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引用次数: 0

LncRNA Mir155hg contributes to hippocampal injury in status epilepticus rats through miR-155/Socs1/NF-κΒ signaling axis LncRNA Mir155hg通过miR-155/Socs1/NF-κΒ信号轴参与癫痫持续状态大鼠海马损伤

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-07-17 DOI: 10.1016/j.jphs.2025.07.005

Yangmei Xie , Ming Wang , Binyuan Xu , Yiye Shao , Yinghui Chen

Background

Neuroinflammation contributes to cognitive deficits in status epilepticus (SE). The lncRNA Mir155hg has been identified as a key regulator of inflammation, but its role in SE remains unclear.

Methods

Mir155hg was knocked down using the adeno-associated virus (AAV) in the rat models of SE. Cognitive function and neuronal damage were assessed using Morris Water Maze and Nissl staining. Inflammatory cytokines (TNF-α, IL-1β) and NF-κB pathway activity were measured by Western blot. Mechanistic insights into Mir155hg-mediated NF-κB regulation were investigated via dual-luciferase assays and co-immunoprecipitation analysis.

Results

Our findings demonstrated that elevated level of Mir155hg was positively correlated with upregulation of TNF-α and IL-1β both in vivo and in vitro. Knockdown of Mir155hg reduced hippocampal inflammation and NF-κB activation. Mechanistically, Mir155hg acted as a competing endogenous RNA to sequester miR-155, thereby suppressing the expression of Socs1, an E3 ligase targeting NF-κB p65 for degradation. Co-immunoprecipitation analysis confirmed the interaction between NF-κB p65 and Socs1.

Conclusions

Mir155hg exacerbates SE-related neuroinflammation via the miR-155/Socs1/NF-κB axis. Targeting this pathway may mitigate SE-induced neuronal injury and cognitive deficits.

背景：神经炎症可导致癫痫持续状态（SE）的认知缺陷。lncRNA Mir155hg已被确定为炎症的关键调节因子，但其在SE中的作用尚不清楚。方法应用腺相关病毒（AAV）在SE大鼠模型中敲低smir155hg。采用Morris水迷宫和尼氏染色评估认知功能和神经元损伤。Western blot检测炎症因子（TNF-α、IL-1β）和NF-κB通路活性。通过双荧光素酶测定和共免疫沉淀分析，研究了mir155hg介导的NF-κB调节的机制。结果Mir155hg在体内和体外均与TNF-α和IL-1β的上调呈正相关。Mir155hg的下调降低了海马炎症和NF-κB的激活。在机制上，Mir155hg作为竞争性内源性RNA隔离miR-155，从而抑制Socs1的表达，Socs1是一种靶向NF-κB p65降解的E3连接酶。共免疫沉淀分析证实了NF-κB p65与Socs1之间的相互作用。结论smir155hg通过miR-155/Socs1/NF-κB轴加重se相关神经炎症。靶向这一途径可能减轻se诱导的神经元损伤和认知缺陷。

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引用次数: 0

Ameliorative effects of Kir4.1 channel inhibitors on lipopolysaccharide-induced cognitive impairment via BDNF/TrkB signaling pathway Kir4.1通道抑制剂通过BDNF/TrkB信号通路改善脂多糖诱导的认知功能障碍

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-07-15 DOI: 10.1016/j.jphs.2025.07.002

Yuto Ishizaki , Saki Shimizu , Ayana Kusaka, Akane Yoshida, Naofumi Kunisawa, Yukihiro Ohno

Inwardly rectifying potassium 4.1 (Kir4.1) channels are predominantly expressed in astrocytes and considered to be involved in the pathogenesis of brain diseases, including depression and epilepsy. In the present study, we evaluated the effects of Kir4.1 channel inhibitors, VU0134992 and quinacrine, on lipopolysaccharide (LPS)-induced cognitive impairment to clarify the role of Kir4.1 channels in controlling cognitive functions. Male BALB/c mice were treated with LPS, with or without Kir4.1 channel inhibitors, for 7 days. Animals were then subjected to novel object recognition (NOR) and rota-rod tests. Immunohistochemical analyses of glia fibrillary acid protein (GFAP) and neuronal nuclei (NeuN) were also performed. Treatment of LPS clearly showed cognitive impairment in the NOR test, which accompanied elevated GFAP- and reduced NeuN-immunoreactivity in hippocampal CA1 and CA3 regions. VU0134992 and quinacrine significantly ameliorated LPS-induced cognitive impairment without affecting rota-rod performance. In addition, both Kir4.1 channel inhibitors suppressed LPS-induced astrocyte activation and attenuated neuronal damage in CA1 and CA3 regions. Furthermore, combined treatments of ANA-12, a TrkB receptor antagonist, with VU0134992 suppressed the ameliorative effects of VU0134992 on cognitive impairment and hippocampal neuronal damage. These results suggest that blockade of astrocytic Kir4.1 channels ameliorates neuroinflammatory cognitive impairment via BDNF/TrkB signaling pathway.

内纠偏钾4.1 （Kir4.1）通道主要在星形胶质细胞中表达，被认为参与包括抑郁症和癫痫在内的脑部疾病的发病机制。在本研究中，我们评估了Kir4.1通道抑制剂VU0134992和quinacrine对脂多糖（LPS）诱导的认知功能障碍的影响，以阐明Kir4.1通道在控制认知功能中的作用。雄性BALB/c小鼠用LPS（含或不含Kir4.1通道抑制剂）治疗7天。然后对动物进行新目标识别（NOR）和旋转棒测试。免疫组化分析神经胶质原纤维酸蛋白（GFAP）和神经元核（NeuN）。LPS治疗在NOR测试中明显显示认知障碍，并伴有海马CA1和CA3区GFAP-升高和neun免疫反应性降低。VU0134992和quinacrine可显著改善lps诱导的认知障碍，但不影响旋转棒的性能。此外，两种Kir4.1通道抑制剂均抑制lps诱导的星形胶质细胞活化，并减轻CA1和CA3区域的神经元损伤。此外，TrkB受体拮抗剂ANA-12与VU0134992联合治疗可抑制VU0134992对认知功能障碍和海马神经元损伤的改善作用。这些结果表明，阻断星形细胞Kir4.1通道可通过BDNF/TrkB信号通路改善神经炎性认知障碍。

{"title":"Ameliorative effects of Kir4.1 channel inhibitors on lipopolysaccharide-induced cognitive impairment via BDNF/TrkB signaling pathway","authors":"Yuto Ishizaki , Saki Shimizu , Ayana Kusaka, Akane Yoshida, Naofumi Kunisawa, Yukihiro Ohno","doi":"10.1016/j.jphs.2025.07.002","DOIUrl":"10.1016/j.jphs.2025.07.002","url":null,"abstract":"<div><div>Inwardly rectifying potassium 4.1 (Kir4.1) channels are predominantly expressed in astrocytes and considered to be involved in the pathogenesis of brain diseases, including depression and epilepsy. In the present study, we evaluated the effects of Kir4.1 channel inhibitors, VU0134992 and quinacrine, on lipopolysaccharide (LPS)-induced cognitive impairment to clarify the role of Kir4.1 channels in controlling cognitive functions. Male BALB/c mice were treated with LPS, with or without Kir4.1 channel inhibitors, for 7 days. Animals were then subjected to novel object recognition (NOR) and rota-rod tests. Immunohistochemical analyses of glia fibrillary acid protein (GFAP) and neuronal nuclei (NeuN) were also performed. Treatment of LPS clearly showed cognitive impairment in the NOR test, which accompanied elevated GFAP- and reduced NeuN-immunoreactivity in hippocampal CA1 and CA3 regions. VU0134992 and quinacrine significantly ameliorated LPS-induced cognitive impairment without affecting rota-rod performance. In addition, both Kir4.1 channel inhibitors suppressed LPS-induced astrocyte activation and attenuated neuronal damage in CA1 and CA3 regions. Furthermore, combined treatments of ANA-12, a TrkB receptor antagonist, with VU0134992 suppressed the ameliorative effects of VU0134992 on cognitive impairment and hippocampal neuronal damage. These results suggest that blockade of astrocytic Kir4.1 channels ameliorates neuroinflammatory cognitive impairment via BDNF/TrkB signaling pathway.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 2","pages":"Pages 64-73"},"PeriodicalIF":3.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144662538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Early temporal suppression of SPARC inhibits oxidative stress, inflammation, and fibrosis in the chronic phase after renal ischemia/reperfusion 早期时间抑制SPARC可抑制肾缺血/再灌注后慢性期的氧化应激、炎症和纤维化

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-07-14 DOI: 10.1016/j.jphs.2025.07.003

Hiroe Toba , Denan Jin , Shinji Takai

Acute kidney injury is associated with not only high morbidity in the acute phase but also the development of chronic kidney disease (CKD). Recently, we found that suppression of secreted protein acidic and rich in cysteine (SPARC) exhibits renoprotective effects in acute ischemia/reperfusion (I/R) injury. The present study investigated the hypothesis that temporal suppression of SPARC in the early stages of I/R-injury might lead to the prevention of renal injury in the chronic phase. The left renal pedicle of male BALB/c mice was occluded for 45 min after right uninephrectomy and subsequently reperfused for 28 days. Small interfering RNA (siRNA) targeting SPARC was injected intravenously 1 day before and 3 days after I/R. Histological assessment revealed that SPARC knockdown by siRNA attenuated tubular injury, tubulointerstitial fibrosis, and the overexpression of 4-hydroxynonenal, a marker of lipid peroxidation. I/R-induced overexpression of a major source of superoxide NADPH oxidase, tumor necrosis factor-α, and matrix metalloproteinase-9 was suppressed by siRNA targeting SPARC. Treatment with siRNA targeting SPARC reduced the expression of a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1), which colocalizes with SPARC. In conclusion, SPARC might be a potential therapeutic target for preventing CKD development following acute I/R injury.

急性肾损伤不仅与急性期的高发病率有关，而且与慢性肾脏疾病（CKD）的发展有关。最近，我们发现抑制酸性和富含半胱氨酸的分泌蛋白（SPARC）在急性缺血/再灌注（I/R）损伤中具有肾保护作用。本研究探讨了在I/ r损伤早期时间抑制SPARC可能导致慢性肾损伤预防的假设。雄性BALB/c小鼠右肾切除后左肾蒂封闭45分钟，再灌注28天。在I/R前1天和后3天静脉注射靶向SPARC的小干扰RNA （siRNA）。组织学评估显示，通过siRNA敲低SPARC可减轻小管损伤、小管间质纤维化和4-羟基壬烯醛（脂质过氧化标志物）的过度表达。I/ r诱导的超氧化物NADPH氧化酶、肿瘤坏死因子-α和基质金属蛋白酶-9的过表达被靶向SPARC的siRNA抑制。靶向SPARC的siRNA治疗降低了与SPARC共定位的具有血小板反应蛋白1型基序（ADAMTS1）的崩解素和金属蛋白酶的表达。总之，SPARC可能是预防急性I/R损伤后CKD发展的潜在治疗靶点。

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引用次数: 0

TPNA10168, an Nrf2 activator, attenuates LPS-induced inflammation in microglia through modulation of MAPK and NF-κB pathways TPNA10168是一种Nrf2激活剂，通过调节MAPK和NF-κB通路，减轻lps诱导的小胶质细胞炎症

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-07-03 DOI: 10.1016/j.jphs.2025.07.001

Yasuhiko Izumi , Eri Koide , Fumika Kobayashi , Saori Ikawa , Midai Takayama , Kouya Yamaki , Norihiko Takeda , Takahiro Yamada , Masafumi Ueda , Toshiaki Kume , Yutaka Koyama

The nuclear factor erythroid 2-related factor 2 (Nrf2)–antioxidant response element (ARE) pathway is a major cellular defense mechanism against oxidative stress through the induction of antioxidant proteins. Chemical inducers of Nrf2 often exhibit anti-inflammatory properties. TPNA10168, originally identified as an Nrf2–ARE activator, has previously been shown to attenuate interferon-γ-induced inflammatory responses in BV-2 microglial cells in an Nrf2-independent manner. However, its anti-inflammatory effects on primary microglia remain unclear. In this study, TPNA10168 significantly suppressed the lipopolysaccharide (LPS)-induced expression of inflammatory genes, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, in primary microglia. The anti-inflammatory effects of TPNA10168 persisted even after Nrf2 knockdown. Mechanistic analysis revealed that TPNA10168 inhibited LPS-induced phosphorylation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and nuclear factor-κB (NF-κB) p65 without affecting NF-κB nuclear translocation. These findings indicate that TPNA10168 attenuates microglial activation by inhibiting proinflammatory signaling pathways, in part through Nrf2-independent pathways, and is a promising compound for modulating neuroinflammation.

核因子红细胞2相关因子2 (Nrf2) -抗氧化反应元件（ARE）通路是细胞通过诱导抗氧化蛋白抵抗氧化应激的主要防御机制。Nrf2的化学诱导剂通常表现出抗炎特性。TPNA10168最初被鉴定为Nrf2-ARE激活剂，先前已被证明以nrf2不依赖的方式减弱干扰素γ诱导的BV-2小胶质细胞炎症反应。然而，其对初级小胶质细胞的抗炎作用尚不清楚。在本研究中，TPNA10168显著抑制脂多糖（LPS）诱导的炎性基因表达，包括肿瘤坏死因子-α、白细胞介素(IL)-1β和IL-6。即使Nrf2敲低，TPNA10168的抗炎作用仍然存在。机制分析显示，TPNA10168抑制lps诱导的细胞外信号调节激酶、p38丝裂原活化蛋白激酶和核因子-κB (NF-κB) p65的磷酸化，但不影响NF-κB核易位。这些发现表明TPNA10168通过抑制促炎信号通路（部分通过nrf2非依赖性通路）来减弱小胶质细胞的激活，是一种有希望调节神经炎症的化合物。

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引用次数: 0

Formalizing and expanding our ethical framework: Introducing the comprehensive ethical guidelines for the Journal of Pharmacological Sciences 规范和扩展我们的伦理框架：为《药理学杂志》介绍全面的伦理准则

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-06-26 DOI: 10.1016/j.jphs.2025.06.007

Junko Kurokawa , Yuji Ikegaya , Tomoyuki Furuyashiki , Naohiko Anzai , Shuhei Tomita , Yasunari Kanda

引用次数: 0

SMTP-44D prevents negative symptoms of diabetic neuropathy by inhibiting sciatic nerve apoptosis SMTP-44D通过抑制坐骨神经凋亡来预防糖尿病神经病变的阴性症状

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-06-26 DOI: 10.1016/j.jphs.2025.06.006

Ayaka Aoki , Keita Shibata , Ryosuke Shinouchi , Keiji Hasumi , Koji Nobe

Diabetic neuropathy (DN) affects more than 50 % of patients with diabetes mellitus (DM). With progression, it causes negative symptoms characterized by sensory numbness. However, no effective treatment drug has been approved for the negative symptoms of DN. In this study, Stachybotrys microspora triprenyl phenol-44D (SMTP-44D), previously reported to inhibit apoptosis and ameliorate axonal damage in immortalized mouse Schwann cells treated with high glucose, was evaluated in a DN mouse model. Streptozocin (STZ)-induced DM models were treated with SMTP-44D for 49 days starting 8 days after STZ administration of SMTP-44D, and effects on mechanical and thermal thresholds, blood flow, and conduction velocity were evaluated. Epoxyeicosatrienoic acid (EET)/dihydroxyeicosatrienoic acid (DHET) measurements in serum, morphological changes in the sciatic nerve, immunohistochemistry, and TUNEL staining were performed to elucidate the mechanism of action. SMTP-44D improved the 11,12-EET/DHET decrease in serum and blood flow in the sciatic nerve. It inhibited sciatic nerve apoptosis and alleviated myelin thinning, thereby preserving the conduction velocity and showing dose-dependent improvements in mechanical and thermal threshold elevation. A hypoglycemic effect with long-term administration is suggested based on the findings. In conclusion, SMTP-44D is a promising therapeutic agent against the negative symptoms of DN.

糖尿病性神经病变（DN）影响50%以上的糖尿病（DM）患者。随着病情发展，会出现以感觉麻木为特征的阴性症状。然而，目前还没有一种有效的药物被批准用于治疗DN的阴性症状。在本研究中，研究人员在DN小鼠模型中对Stachybotrys microspora triprenyl pheno - 44d （SMTP-44D）进行了研究，该研究先前报道了SMTP-44D在高糖处理的永生化小鼠雪万细胞中抑制凋亡并改善轴突损伤。从STZ给予SMTP-44D后8天开始，用SMTP-44D治疗STZ诱导的DM模型49天，观察其对机械阈值、热阈值、血流量和传导速度的影响。采用血清环氧二碳三烯酸(EET)/二羟基二碳三烯酸（DHET）测定、坐骨神经形态学变化、免疫组化、TUNEL染色等方法探讨其作用机制。SMTP-44D改善了血清和坐骨神经血流中11,12- eet /DHET的下降。它抑制坐骨神经凋亡，减轻髓鞘变薄，从而保持传导速度，并在机械和热阈值升高方面表现出剂量依赖性改善。根据研究结果，建议长期服用具有降糖作用。综上所述，SMTP-44D是一种很有前景的治疗DN阴性症状的药物。

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引用次数: 0

Phenylalanine amide derivatives promote FLG expression via AHR activation in normal human epidermal keratinocytes 苯丙酰胺衍生物通过AHR激活在正常人表皮角质形成细胞中促进FLG表达

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-06-23 DOI: 10.1016/j.jphs.2025.06.005

Akiko Sumitomo , Ratklao Siriwach , Makio Higuchi , Quynh Anh Ngo , Nobuo Tanaka , Somsak Prasongtanakij , Dean Thumkeo , Shuh Narumiya

Filaggrin (FLG) is one of the major components expressed in terminally differentiated keratinocytes and critical for skin barrier functions. It is known that reduced FLG expression causes skin barrier dysfunctions and results in atopic dermatitis (AD). Restoring FLG expression therefore may serve as an effective therapeutic strategy against AD. Using normal human epidermal keratinocyte (NHEK), we identified a phenylalanine amide derivative, termed Compound 8.1, that promotes expression of FLG and other skin barrier-related genes in NHEKs. Gene expression profiling by microarray suggested that Compound 8.1 promotes FLG expression through activation of the aryl hydrocarbon receptor (AHR). Interestingly, compared to a typical AHR activator, FICZ (6-Formylindolo[3,2-b]carbazole), Compound 8.1 preferentially upregulated the expression of genes related to keratinocyte differentiation and skin barrier function in an AHR-dependent manner, but induced a conventional AHR target gene involved in cellular toxicity, CYP1A1, to a significantly lesser extent. Structure-activity relationship analysis further demonstrates that the structural modification of Compound 8.1 could dissociate induction of skin barrier-related gene expression from CYP1A1-dependent metabolism of xenobiotics in AHR actions. Together, our results suggest that Compound 8.1 serves as a prototype compound for developing novel AHR-activating drugs to treat skin barrier dysfunctions without toxicity.

聚丝蛋白（Filaggrin， FLG）是终分化角质形成细胞中表达的主要成分之一，对皮肤屏障功能至关重要。众所周知，FLG表达减少会导致皮肤屏障功能障碍并导致特应性皮炎（AD）。因此，恢复FLG表达可能是对抗AD的有效治疗策略。使用正常的人表皮角质细胞（NHEK），我们发现了一种苯丙氨酸酰胺衍生物，称为化合物8.1，可促进FLG和其他皮肤屏障相关基因在NHEK中的表达。基因表达谱分析表明，化合物8.1通过激活芳烃受体（AHR）促进FLG的表达。有趣的是，与典型的AHR激活剂FICZ （6-Formylindolo[3,2-b]carbazole）相比，化合物8.1以AHR依赖的方式优先上调与角质形成细胞分化和皮肤屏障功能相关的基因的表达，但诱导参与细胞毒性的传统AHR靶基因CYP1A1的程度要小得多。构效关系分析进一步表明，化合物8.1的结构修饰可以将AHR作用中皮肤屏障相关基因表达的诱导与cyp1a1依赖性外源代谢分离。总之，我们的研究结果表明，化合物8.1可以作为开发新型ahr激活药物的原型化合物，用于治疗皮肤屏障功能障碍而没有毒性。

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引用次数: 0